Controlling the flow of a powder

ABSTRACT

An apparatus for filling a receptacle with a powder comprises a hopper adapted to contain a powder pharmaceutical formulation, the hopper comprising an outlet. A vibratable member is positioned in, on, or near the hopper so that the vibratable member is spaced from powder in the hopper, and the vibratable member is capable of fluidizing the powder in the hopper. Powder flowing through the outlet under the control of the vibratable member flows into a receptacle or into a transfer chamber for transport to a receptacle.

[0001] This application claims the benefit of U.S. Provisional PatentApplication Serial No. 60/392,076, filed on Jun. 27, 2002, which isincorporated herein by reference in its entirety.

BACKGROUND

[0002] The need for effective therapeutic treatment of patients hasresulted in the development of a variety of techniques for delivering apharmaceutical formulation to a patient. One traditional techniqueinvolves the oral delivery of a pharmaceutical formulation in the formof a pill, capsule, or the like. Inhaleable drug delivery, where anaerosolized pharmaceutical formulation is orally or nasally inhaled by apatient to deliver the formulation to the patient's respiratory tract,has also proven to be an effective manner of delivery. In one inhalationtechnique, a pharmaceutical formulation is delivered deep within apatient's lungs where it may be absorbed into the blood stream. Inanother inhalation technique, a pharmaceutical formulation is deliveredto a targeted region in the respiratory tract to provide local treatmentto the region. Many types of inhalation devices exist including devicesthat aerosolize a dry powder pharmaceutical formulation.

[0003] The pharmaceutical formulation is often packaged so that it maybe made easily available to a user. For example, a dose or a portion ofa dose may be stored between layers of a multi-layered package,conventionally referred to as a blister or blister pack. Typically, acavity is formed in a lower layer, the pharmaceutical formulation isdeposited within the cavity, and an upper layer is sealed onto the lowerlayer, such as by heating and/or compressing the layers, to secure thepharmaceutical formulation within the cavity. Alternatively, the dosemay be stored in a capsule that is to be swallowed or from which thepharmaceutical formulation may be aerosolized. Other packages, such asbottles, vials, and the like, may also be used to store thepharmaceutical formulation.

[0004] It is often difficult to effectively fill packages with thepharmaceutical formulation. For example, during a powder fillingprocess, it is difficult to sufficiently fluidize the powder and/or tomaintain consistent flow properties of the powder. Poorly controlledpowder flow can result in inconsistently filled packages. For example,the fill mass may vary from package to package thereby affecting thedose to be delivered to a patient for a unit dose package or resultingin too many or too few doses being packaged in a multi-dose package.Additionally, the packing characteristics of a powder in a package mayvary as a result of inconsistent powder flow during the filling process.

[0005] Therefore, it is desirable to be able to control the flow of apowder, particularly a powder pharmaceutical formulation. It is furtherdesirable to be able to control the flow of a powder pharmaceuticalformulation so that a package may be effectively and consistently filledwith the pharmaceutical formulation. It is still further desirable tocontrol the flow of a pharmaceutical formulation in a manner thatreduces any adverse effects on the pharmaceutical formulation.

SUMMARY

[0006] The present invention satisfies these needs. In one aspect of theinvention the flow of powder from a hopper is controlled in an improvedmanner.

[0007] In another aspect of the invention, an apparatus for filling achamber comprises a hopper adapted to contain a powder pharmaceuticalformulation, the hopper comprising an outlet. The apparatus alsocomprises a disturbance member capable of disturbing a medium within thehopper, the disturbance of the medium being sufficient to control theflow of powder through the outlet. The chamber may be filled by powderflowing through the outlet and into the chamber.

[0008] In another aspect of the invention, an apparatus for filling achamber comprises a hopper adapted to contain a powder pharmaceuticalformulation, the hopper comprising an outlet. The apparatus alsocomprises a vibratable member positioned in, on, or near the hopper sothat the vibratable member is spaced from powder in the hopper, thevibratable member being capable of fluidizing the powder in the hopper.The chamber may be filled with powder flowing through the outlet andinto the chamber.

[0009] In another aspect of the invention, a method of filling a chambercomprises providing a powder pharmaceutical formulation in a hopper;disturbing a medium in the hopper to fluidize the powder; and passingthe powder through an outlet and into the chamber.

[0010] In another aspect of the invention, a method of filling a chambercomprises providing a powder pharmaceutical formulation; vibrating amember spaced from the powder to fluidize the powder; and passing thepowder through an outlet and into the chamber.

[0011] In another aspect of the invention, a pharmaceutical package ismade by a process comprising providing a receptacle; filling thereceptacle with a powder pharmaceutical formulation that has beenfluidized by a fluidization member spaced from the powder; and sealingthe receptacle to secure the powder pharmaceutical formulation therein.

DRAWINGS

[0012] These features, aspects, and advantages of the present inventionwill become better understood with regard to the following description,appended claims, and accompanying drawings which illustrate exemplaryfeatures of the invention. However, it is to be understood that each ofthe features can be used in the invention in general, not merely in thecontext of the particular drawings, and the invention includes anycombination of these features, where:

[0013]FIG. 1 is a schematic sectional side view of a powder fillingapparatus of the invention;

[0014]FIGS. 2A through 2C are schematic sectional side views of variousreceptacles that may be filled using the powder filling apparatus of theinvention;

[0015]FIG. 3 is a schematic sectional side view of another version of apowder filling apparatus;

[0016]FIGS. 4A and 4B are schematic sectional side views of theoperation of another version of a powder filling apparatus;

[0017]FIG. 5 is a schematic sectional side view of another version of apowder filling apparatus;

[0018]FIGS. 6A and 6B are schematic sectional side views of the powderfilling apparatus of FIG. 5 during a powder filling process;

[0019]FIG. 7 is a schematic sectional front view of a multiple chamberpowder filling apparatus;

[0020]FIGS. 8A and 8B are schematic sectional front views of otherversions of multiple chamber powder filling apparatus;

[0021]FIG. 9 is a schematic cut-away view showing the interior of aversion of a powder filling apparatus;

[0022]FIG. 10 is a schematic sectional side view of a powder fillingapparatus together with a bulk powder container; and

[0023]FIG. 11 is a more detailed schematic sectional side view of aversion of a powder filling apparatus with a bulk powder container.

DESCRIPTION

[0024] The present invention relates to controlling the flow of apowder, such as by controlling the flow of powder during a packagefilling process. Although the process is illustrated in the context ofpackaging a powder pharmaceutical formulation, the present invention canbe used in other processes and should not be limited to the examplesprovided herein.

[0025] A powder filling apparatus 100 according to the present inventionis shown schematically in FIG. 1. The powder filling apparatus 100comprises a hopper 105 having a reservoir 110 capable of containing abed of powder 115, such as a powder pharmaceutical formulation. Thehopper 105, which may be of any suitable size and shape, comprises anoutlet 120 through which fluidized powder may flow. A chamber 125 may bepositioned in proximity to the outlet 120 so that powder flowing throughthe outlet 120 will flow into the chamber 125 to fill the chamber 125.

[0026] A powder fluidizer 130 may be positioned in, on, or near thehopper 105. The powder fluidizer 130 comprises a disturbance member 135that provides a disturbance within the hopper 105. In one version, thedisturbance member 135 may be actuated by an actuator 140 to cause adisturbance within the hopper 105 to control the flow of powder 115 inthe hopper 105. For example, the disturbance member 135 may disturb amedium 145, such as air or other gas, that is in the hopper 105 in sucha manner that the disturbed medium 145 may cause fluidization of thepowder 115. Accordingly, at least a portion of the disturbance member135 may be positioned so that it is separated from the powder 115 by themedium 145.

[0027] The powder fluidizer 130 may be used to control a powder fillingprocess within the hopper 105. In one version, the powder fluidizer 130may operate continuously or periodically in short intervals to maintainthe powder 115 in a constantly fluidized state. In this version, powder115 may flow through the outlet 120 until the hopper 105 is empty oruntil the chamber 125 is filled. In another version, the powderfluidizer 130 may control the timing of the flow of powder 115 and/ormay control the amount of powder 115 that flows through the outlet 120of the hopper 105 and into the chamber 125. For example, the outlet 120in the hopper 105 may be sufficiently small that undisturbed powder 115does not flow through the outlet 120 or does not consistently flowthrough the outlet 120. When it is desired for the powder 115 to flowinto the chamber 125, the actuator 140 causes the disturbance member 135to disturb the medium 145 and thereby fluidize the powder 115 to allowthe powder 115 to flow through the outlet 120 and into the chamber 125.When the chamber 125 is sufficiently filled, the actuator 140 may causethe disturbance to stop or be reduced, thereby reducing the amount ofpowder 115 flowing through the outlet 120, for example by terminatingthe flow of powder through the outlet 120.

[0028] In one version, the powder fluidizer 130 provides a disturbancewithin the hopper 105, and the disturbance comprises vibrations 150. Thedisturbance member 135 may comprise a vibratable object, such as amembrane 155, within, on or near the hopper 105, the membrane 155 beingcapable of vibrating when excited by the actuator 140 to producevibrations. The vibrating membrane 155 disturbs the medium 145. Forexample, as the membrane 155 moves in a downward direction, the portionof the medium 145 immediately in front is compressed causing a slightincrease in pressure, it then moves back past its rest position andcauses a reduction in the pressure. The process may continue so that oneor more waves of alternating high and low pressure are radiated awayfrom the membrane 155. The waves contact the powder 115 and theresulting impact is sufficient to at least momentarily fluidize thepowder 115.

[0029] The frequency of the vibrations 150 may be selected to fluidize aparticular powder 115 and/or to best suit a particular filling process.In one particular version, the vibrations 150 may be in the audiblerange. In yet another version, the membrane 155 may vibrate at afrequency in a non-audible range to lessen operator annoyance. Thevibration may be at any frequency, or multiple frequencies, thatdesirably fluidizes or otherwise controls the flow of the powder 115.For example, in the version shown in FIG. 1, the membrane 155 mayvibrate at one or more frequencies comprising a frequency of from about10 Hz to about 1000 Hz, more preferably from about 90 Hz to about 500Hz, more preferably from about 100 Hz to about 200 Hz, and mostpreferably at about 120 Hz. In one version, the frequency may beselectable. For example, through experimentation or modeling, aparticularly desirable frequency for a particular configuration and/orpowder may be selected, such as a frequency that is determined throughexperimentation or analysis to cause a resonance within the hopper 105.

[0030] The chamber 125 comprises an opening 160 positionable in relationto the outlet 120 in the hopper 105 to receive powder flowing from thehopper 105 through the outlet 120. In one version, such as the versionshown in FIG. 1, the opening 160 into the chamber 125 is substantiallythe same shape and size and as the outlet 120 to prevent excessiveamounts of powder 115 from getting trapped between the hopper 105 and amember 165 that contains or supports the chamber 125. As also shown inthe version of FIG. 1, the hopper 105 may comprise converging side walls170 that provide a convergent flow path towards the outlet 120 for thepowder 115. The convergent flow path allows for increased reservoirvolume in the hopper 105. In another version, the chamber opening 160and the outlet 120 may be differently sized. For example, the outlet 120may be smaller than the opening 160 when it is desirable to fill arelatively large chamber with a precisely controlled amount of powder115 or when it is not desirable to provide a mechanism for preciselypositioning the chamber 125 beneath the outlet 120. Alternatively, theopening 160 may be smaller than the outlet 120 when it is desirable touse the hopper 105 to fill varying sizes of chambers 125 or insituations where the loss of powder 115 to spaces between the hopper 105and the member 165 is not of critical concern.

[0031] The chamber 125 may be within a receptacle 175 used to store thepowder 115. For example, the receptacle 175 may be in the form ofprimary or secondary packaging used to store a powder pharmaceuticalformulation. In one version, the receptacle 175 comprises amulti-layered package, conventionally referred to as a blister orblister pack, and the chamber 125 is within the multi-layered package.As shown in FIG. 2A, powder 115 flows from the hopper 105 to a cavity180 in a lower layer 185 of the multi-layered package. An upper layer(not shown) may then be sealed onto the lower layer 185, such as byheating and/or compressing the layers, to secure the powder within thecavity 180, as described for example in U.S. Pat. No. 5,865,012 and inU.S. patent application Ser. No. 10/301,820, filed on Nov. 20, 2002,both of which are incorporated herein by reference in their entireties.In one version, the multi-layered package may comprise a lower layercomprising a metal containing layer, such as a layer comprisingaluminum, and/or an upper layer comprising a metal containing layer. Themetal containing layers may be sufficiently thick to substantiallyprevent a significant amount of moisture from passing therethrough. Forexample, the metal containing layers may be from about 10 μm to about100 μm, and more preferably from about 20 μm to about 80 μm. The lowerlayer and the upper layer may be sealed together by a layer of sealingmaterial, such as a layer of lacquer that may be from about 1 μm toabout 20 μm. In another version, the receptacle 175 comprises a capsule,such as a capsule that is to be swallowed or from which thepharmaceutical formulation may be aerosolized, and the chamber 125 iswithin the capsule. As shown in FIG. 2B, a first portion 190 of acapsule is positioned to receive powder flowing through the outlet 120of the hopper. After filling, a second portion (not shown) may be placedover the first portion 190 to form the a capsule shape and to containthe powder within the capsule, as described in U.S. Pat. No. 4,247,066,U.S. Pat. No. 4,864,876, U.S. Pat. No. 6,357,490, and in the PCTapplication WO 00/07572 published on Feb. 17, 2000, all of which areincorporated herein by reference in their entireties. In anotherversion, as shown in FIG. 2C, the chamber 125 may be within a container195, such as a bottle, vial or the like. For example, in this version,the container 195 may be use to contain multiple doses of a powderpharmaceutical formulation, such as a container described in U.S. Pat.No. 4,524,769 which is incorporated herein by reference in its entirety.

[0032] In another version, the chamber 125 may be a transfer chamber 200that transfers powder that flows from the hopper 115 into the transferchamber 200 to another chamber, such as a chamber within a package 175.For example, as shown in FIG. 3, the transfer chamber 200 may beprovided in a movable member 205. The transfer chamber 200 receivespowder from the hopper 115 when in a filling position as shown in FIG.3. The movable member 205 then transports the transfer chamber 200 to aposition in proximity to the package 175 where at least a portion of thecontents of the transfer chamber 200 may be emptied into the package175. The transport chamber 200 may be sized so that it contains apredetermined amount of powder. For example, the transport chamber 200may be sized to collect a dose of a powder pharmaceutical formulation,and the accurate dose may be delivered to the package 175. A doctorblade 210 may be provided to scrape off any excess powder in thetransport chamber 200.

[0033] In the version shown in FIGS. 4A and 4B, a powder transferassistance mechanism 215 is provided. In one version, the powdertransfer assistance mechanism 215 comprises a channel 220 incommunication with the transfer chamber 200. The channel 200 isconnectable to a source of suction when the transfer chamber 200 is inthe powder collecting position shown in FIG. 4A. In this way, suction225 can be provided to the transfer chamber 200 to assist in collectingpowder 115 within the transfer chamber 200. A filter 230 may be providedin the transfer chamber 200 to prevent powder 115 from being suctionedinto the channel 200. For example, the filter may comprise apertureshaving a diameter of from about 0.10 micrometers to about 0.65micrometers, most preferably about 0.65 micrometers. When the transferchamber 200 is moved to a powder ejecting position as shown in FIG. 4B,the channel 220 may be connectable to a source of pressurized gas tocreate pressure 235 within the channel 220 to cause the powder in thetransfer chamber 200 to be ejected into the receptacle 175. An exampleof a powder transfer assistance mechanism is described in U.S. Pat. No.5,826,633, which is incorporated herein by reference in its entirety.

[0034] The powder filling apparatus 100 provides for an advantageouspowder filling process. One such advantage is that there is a reductionin the amount of physical contact between powder in the hopper 105 andother objects. This reduced contact can be useful in preventingundesirable conditions in the powder pharmaceutical formulation. Forexample, excessive physical contact can in some situations cause one ormore of the following situations: formation of aggregates, increasedelectrostatic interactions, denaturation, and reduced aerosolperformance. Though these undesirable effects have been prevented orcompensated for in costly and encumbering manners, the reduction of theamount of direct physical contact provides a particularly simplified anduseful alternative.

[0035] In another version, the powder filling apparatus 100 comprises apowder fluidizer 130 of the type discussed above in combination with anadditional powder fluidizing member. For example, as shown in FIG. 5,the powder filling apparatus may comprise a second powder fluidizer 240.The second powder fluidizer 240 comprises a powder fluidizing member 250and an actuator 255 that drives the powder fluidizing member 250 to in amanner that fluidizes the powder 115 in the hopper 105. For example, thepowder fluidizing member 250 may be a member that directly contacts thepowder 115, and the movement of the fluidizing member 250 causes thepowder 115 to fluidize. In the version shown, the powder fluidizingmember 250 comprises a rod 260 that extends downwardly into the bed ofpowder 115. A holding arm 265 holds the rod 260 in the hopper 105. Theactuator 255 may be connected to drive the arm 265 to drive the rod 260or may be connected directly to the rod 260, such as by being connectedbetween the rod 260 and the arm 265. The fluidization of powder in thismanner is described in U.S. Pat. No. 6,182,712 which is incorporatedherein by reference in its entirety. The rod 260 may be caused tovibrate by the actuator 240. For example, as shown in FIG. 5, the rodmay have a distal end that is positionable near the outlet 120, and theactuator 240 may drive the rod in an up and down motion 270 to fluidizethe powder to cause it to flow through the outlet 120 and into thechamber 125. In one particular version, the rod 260 may be attached to amotor, such as a piezoelectric motor, and is vibrated at a frequency offrom about 1000 Hz to about 180,000 Hz, more preferably from about10,000 Hz to about 40,000 Hz, and most preferably from about 15,000 Hzto about 25,000 Hz. Additionally or alternatively, the rod 260 may bevibrated or moved in another direction, such as laterally orrotationally. In another version, the additional powder fluidizingmember may comprise a stirrer or other fluidizing mechanism.

[0036] The powder fluidizer 130 and second powder fluidizer 240 may workin tandem or alone to fluidize powder 115 in the hopper 105. Forexample, as shown in FIG. 5, the powder fluidizer 130 may be actuatedconcurrently with the second powder fluidizer 240 to simultaneouslygenerate vibrations 150 in the medium 145 and to directly vibrate 270the powder 115. For some powders this combined action provides superiorfluidization capabilities. In another version, the powder fluidizer 130and the second powder fluidizer 240 may be actuated at different timesor actuated in a manner to supplement one another. For example, as shownin FIGS. 6A and 6B, the powder fluidizer 130 may serve to supplement theaction of the second powder fluidizer 240. As shown in FIG. 6A, for somepowders, the vibration of the rod 260 may be sufficient for a chamber125 to be filled but may also result in the formation of one or morevoids 275 in the area in proximity to the rod 260. After the void 275has been created, vibration of the rod 260 would have littlefluidization capability. To fill the void 275, the powder fluidizer 130may be actuated, as shown in FIG. 6B. The disturbance to the medium 145is sufficient to cause the powder 115 to again contact the rod 260 sothat the rod 260 may again be vibrated to fluidize the powder 115. Thepowder fluidizer 130 and/or the second powder fluidizer 240 may operatecontinuously to maintain the powder 115 in a continuously fluidizedcondition during the filling of multiple chambers 125 through the outlet120. Alternatively, the powder fluidizer 130 and/or the second powderfluidizer 240 may operate only when it is desired to have the powder 115fluidized, and the outlet 120 may be sized such that the powder does notsubstantially flow though the outlet 120 in the absence of suchoperation of the fluidizers.

[0037] In one version, as shown in FIG. 7, the powder filling apparatus100 is configured to simultaneously fill a plurality of chambers 125. Inthis version the hopper 105 comprises a plurality of outlets 120, suchas two, three, four, or more. The powder fluidizer 130 is positioned tofluidize the powder 115 in the hopper 105 across all of the outlets 120.In the version shown in FIG. 7, the powder flowing through an outlet 120passes into a transfer chamber 200 in a moveable member 205, which inthis version is a rotatable member. When the transfer chamber 200 isfilled, the moveable member 205 is rotated from the filling positionshown in the figure to an ejecting position where the transfer chambers200 are positioned above respective receptacles 175. The receptacles 175are supported by a platform 300. The platform 300 may be moveablerelative to the moveable member 205 so as to able to bring thereceptacles 175 into the position shown in FIG. 7 and to take thereceptacles 175 away after they are filled, at which time the transferchambers 200 are moved back to their filling positions. This process maycontinue until a desired number of receptacles have been filled. In oneversion, the platform 300 may be a moveable and indexable plate havingopenings for receiving receptacles. In another version, the platform 300may be a belt on a roller system.

[0038]FIGS. 8A and 8B show versions of a powder filling apparatus 100capable of simultaneously filling a plurality of chambers 120 andcomprising a powder fluidizer 130 and a second powder fluidizer 240. Inthe version of FIG. 8A, the second powder fluidizer 240 comprises a rod260 that may be vibrated in an up and down direction 270. In addition, amechanism is provided that allows the rod 260 to translate laterally 310across each of the openings. An exemplary translation mechanism isdescribed in aforementioned U.S. Pat. No. 6,182,71.2 which isincorporated herein by reference, as discussed above. In the version ofFIG. 8B, a plurality of vibrating rods 260 are provided. For example, arod 260 may be associated with a respective outlet 120.

[0039] A detailed view of an embodiment of a powder filling apparatus inaccordance with the version of FIG. 8A is shown in FIG. 9. In thisversion, a power fluidizer 130 and a second powder fluidizer 240 areused to control the flow of powder in the hopper through a plurality ofoutlets 120. The rod 260 of the second powder fluidizer is connected toa piezoelectric actuator or motor 320 to cause the rod 260 to vibrate upand down. A mechanism, such as a screw drive, is provided within the arm265 that causes the rod 260 to translate 310 across the hopper 105. Afirst enclosure 325 and a second enclosure 330 are provided to maintaindesirable conditions within the powder filling apparatus 100. Forexample, for some powders, such as powder pharmaceutical formulations,it may be desirable to maintain a clean or sterile environment for thepowder. It may also be desirable to maintain a certain relative humiditywithin enclosures, particularly when filling powders that undergo achange when subjected to significant amounts of moisture. One or more ofthe enclosures may comprise, for example, a medical grade stainlesssteel, engineering polymer, PVC, or the like. In one version, multiplepowder fluidizers 130 may be provided within the second enclosure. Thismay be advantageous when very large hoppers 105 are utilized. An inlet335 through the enclosure 325 allows for the introduction of bulk powderinto the hopper 105.

[0040] At least a portion of the powder fluidizer 130 may be housedwithin the second enclosure 330. In one version, the membrane 155 may bea portion of a speaker cone from a conventional audio speaker. Thespeaker is connected to a function generator that can provide power andfrequency ranges to the speaker through an amplifier. As the speakercone vibrates, fluidizing sound is created. The speaker cone maycomprise, for example, a 3 inch woofer, a 4 inch woofer, a 6.5 inchwoofer, or the like. In another version, the powder fluidizer maycomprise a membrane that is spaced from the speaker cone so that whenthe speaker cone vibrates, the membrane is caused to vibrate. Thisconfiguration may be useful in maintaining a controlled environmentwithin the hopper 105 in that the speaker may be housed completelywithin the second enclosure 330 and is not directly exposed to thehopper 105.

[0041] Additionally or alternatively, a bulk powder fluidizer 350 may beprovided to fluidize bulk powder 355 contained in a bulk powdercontainer 360. The bulk powder container 360 may be used to supplypowder to the hopper 105, as shown in FIG. 10. In this version, the bulkpowder container 360 comprises an outlet 365 that is in communicationwith the inlet 335 into the hopper 105. The bulk powder fluidizer 350,which may comprise a membrane 370 and actuator 375 similar to thosedescribed above, is actuated when it is desired to fluidize the bulkpowder 355 to cause it to flow through the outlet 365 and into thehopper 105. This actuation may be continuous so that a small amount ofpowder is continuously being supplied to the hopper 105 at about therate that powder is flowing through the one or more outlets 120 in thehopper 105. Alternatively, the actuation may be periodic. In oneversion, the bulk powder fluidizer 350 may be actuated when the level ofthe powder in the hopper 105 falls below a predetermined level. This mayinvolve manual actuation or a level sensor, such as a capacitive sensor,may be provided to allow for automatic refilling. A gate or valve mayalso be provided near the inlet 335.

[0042] A powder filling apparatus 100 incorporating the features of theversion of FIGS. 9 and 10 is shown in FIG. 11. In this version, a valve380, is provided to selectively introduce powder for the bulk powdercontainer 360 into the hopper 115. In this version, the valve 380 isopened when the level of the powder bed 115 in the hopper 105 fallsbelow a predetermined level. The bed level is detected by a capacitivesensor 385 operatively positioned to generate a signal when the bedlevel falls below the predetermined height. The signal is provided to acontroller which controls the opening and closing of the valve 380.Alternatively or additionally, a laser sensor may be utilized. In theversion shown, a second enclosure 390 is also provided for at least aportion of the bulk powder fluidizer 350.

[0043] The powder filling apparatus 100 has been found to fill powderinto receptacles in an improved manner. The powder filling apparatus 100is particularly effective in filling fine dry powders into unit dosereceptacles. For example, Table 1 shows a comparison of filling a finedry, powder pharmaceutical formulation, Powder A, using a prior artpowder filler and using a powder filling apparatus 100 according to thepresent invention. The prior art powder filler is described in U.S. Pat.No. 6,182,712. The powder filling apparatus 100 shown in present FIG. 11with a transfer chamber as shown in FIGS. 4A and 4B was used for thecomparison. In the Table, N represents the number of receptacles filled;SD represents the standard deviation; and RSD represents the relativestandard deviation. As can be seen, in each of five separate runs, theprior art system was unable to match the filling consistency of thepowder filling apparatus 100. In fact, in even the best run using theprior art system, the filling range was more than twice the range usingthe powder filling apparatus 100 of the present invention. TABLE 1 SDRSD Mean Fill Range Filler Used N (mg) (%) Mass (mg) (mg) Prior ArtPowder Filler, Run 1 404 0.11 1.5 7.52 1.2 Prior Art Powder Filler, Run2 264 0.18 2.5 7.55 1.94 Prior Art Powder Filler, Run 3 491 0.16 2.17.52 1.11 Prior Art Powder Filler, Run 4 488 0.15 2.0 7.51 1.39 PriorArt Powder Filler, Run 5 356 0.32 4.3 7.50 1.99 Present Powder Filler100 288 0.08 1.1 7.50 0.55

[0044] The powder filling apparatus 100 of the present invention hasalso shown universal adaptability for filling various powders. Thepowder filling apparatus 100 shown in present FIG. 11 with a transferchamber as shown in FIGS. 4A and 4B was used for a comparison ofdifferent powders, and the results are shown in Table 2. Six differentpowders were filled into unit dose receptacles. The powders were ofvarying size, compositions, active agents, excipients, and properties.However, as can be seen from the data, very consistent filling wasachieved with each of the powders. Very low RSD's were achieved for eachof the powders. In addition, the powder filling apparatus 100demonstrated the ability to consistently fill both small and large dosesinto a receptacle. TABLE 2 Powder Filled Using Present RSD Mean FillPowder Filler 100 N SD (mg) (%) Mass (mg) Range (mg) Powder A 288 0.081.1 7.50 0.59 Powder B 120 0.03 0.9 4.06 0.16 Powder C 60 0.06 1.2 4.900.28 Powder D 270 0.91 1.8 50.09 4.90 Powder E 89 0.55 1.1 51.32 3.04Powder F 30 0.18 1.8 10.09 0.82

[0045] A computer controller may be provided to control the actuation ofthe bulk powder fluidizer 350 and/or to control the actuation of thepowder fluidizer 130 and/or the second powder fluidizer 240. Thecontroller may control the operation of the entire powder fillingapparatus 100. The controller may be a single controller device or maybe a plurality of controller devices that may be connected to oneanother or a plurality of controller devices that may be connected todifferent components of the packaging apparatus 100.

[0046] In one embodiment, the controller comprises electronic hardwareincluding electrical circuitry comprising integrated circuits that issuitable for operating or controlling the powder filling apparatus 100.Generally, the controller is adapted to accept data input, runalgorithms, produce useful output signals, and may also be used todetect data signals from one or more sensors and other devicecomponents, and to monitor or control the process in the powder fillingapparatus 100. However, the controller may merely perform one of thesetasks. In one version, the controller may comprise one or more of (i) acomputer comprising a central processor unit (CPU) which isinterconnected to a memory system with peripheral control components,(ii) application specific integrated circuits (ASICs) that operateparticular components of the powder filling apparatus 100 or operate aparticular process, and (iii) one or more controller interface boardsalong with suitable support circuitry. Typical CPUs include thePowerPC™, Pentium™, and other such processors. The ASICs are designedand preprogrammed for particular tasks, such as retrieval of data andother information from the powder filling apparatus 100 and/or operationof particular device components. Typical support circuitry includes forexample, coprocessors, clock circuits, cache, power supplies and otherwell known components that are in communication with the CPU. Forexample, the CPU often operates in conjunction with a random accessmemory (RAM), a read-only memory (ROM) and other storage devices wellknown in the art. The RAM can be used to store the softwareimplementation of the present invention during process implementation.The programs and subroutines of the present invention are typicallystored in mass storage devices and are recalled for temporary storage inRAM when being executed by the CPU.

[0047] The software implementation and computer program code product ofthe present invention may be stored in a memory device, such as anEPROM, and called into RAM during execution by the controller. Thecomputer program code may be written in conventional computer readableprogramming languages, such as for example, assembly language, C, C″,Pascal, or native assembly. Suitable program code is entered into asingle file, or multiple files, using a conventional text editor andstored or embodied in a computer-usable medium, such as a memory of thecomputer system. If the entered code text is in a high level language,the code is compiled to a compiler code which is linked with an objectcode of precompiled windows library routines. To execute the linked andcompiled object code, the system user invokes the object code, causingthe computer system to load the code in memory to perform the tasksidentified in the computer program.

[0048] In one version, the controller may comprise a microprocessor orASIC of sufficiently small size and power consumption to be housed on orin the powder filling apparatus 100. For example, suitablemicroprocessors for use as a local microprocessor include theMC68HC711E9 by Motorola, the PIC16C74 by Microchip, and the 82930AX byIntel Corporation. The microprocessor can include one microprocessorchip, multiple processors and/or co-processor chips, and/or digitalsignal processor (DSP) capability.

[0049] In one particularly useful implementation, the powder fillingapparatus 100 may be used to fill a pharmaceutical receptacle, such as ablister, capsule, vial, bottle, or the like, with a powderpharmaceutical formulation. For example, the powder filling apparatus100 has proven to be particularly advantageous in filling dry powderinhaleable pharmaceutical formulations into receptacles from which thepharmaceutical formulation may be aerosolized for inhalation by a user.For example, when in a powdered form, the powder may be initially storedin the sealed package, which is opened prior to aerosolization of thepowder, as described in U.S. Pat. No. 5,785,049, U.S. Pat. No.5,415,162, and U.S. patent application Ser. No. 09/583,312.Alternatively the powder may be contained in a capsule, as described inU.S. Pat. No. 4,995,385, U.S. Pat. No. 3,991,761, U.S. Pat. No.6,230,707, and PCT Publication WO 97/27892, the capsule being openablebefore, during, or after insertion of the capsule into an aerosolizationdevice. In either the bulk, blister, capsule, or the like form, thepowder may be aerosolized by an active element, such as compressed air,as described in U.S. Pat. No. 5,458,135, U.S. Pat. No. 5,785,049, andU.S. Pat. No. 6,257,233, or propellant, as described in U.S. patentapplication Ser. No. 09/556,262, filed on Apr. 24, 2000, and entitled“Aerosolization Apparatus and Methods”, and in PCT Publication WO00/72904. Alternatively the powder may be aerosolized in response to auser's inhalation, as described for example in the aforementioned U.S.patent application Ser. No. 09/583,312 and U.S. Pat. No. 4,995,385. Allof the above references being incorporated herein by reference in theirentireties.

[0050] The pharmaceutical formulation may comprise an active agent. Theactive agent described herein includes an agent, drug, compound,composition of matter or mixture thereof which provides somepharmacologic, often beneficial, effect. This includes foods, foodsupplements, nutrients, drugs, vaccines, vitamins, and other beneficialagents. As used herein, the terms further include any physiologically orpharmacologically active substance that produces a localized or systemiceffect in a patient. An active agent for incorporation in thepharmaceutical formulation described herein may be an inorganic or anorganic compound, including, without limitation, drugs which act on: theperipheral nerves, adrenergic receptors, cholinergic receptors, theskeletal muscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, pulmonary system, autacoidsystems, the alimentary and excretory systems, the histamine system, andthe central nervous system. Suitable active agents may be selected from,for example, hypnotics and sedatives, psychic energizers, tranquilizers,respiratory drugs, anticonvulsants, muscle relaxants, antiparkinsonagents (dopamine antagnonists), analgesics, anti-inflammatories,antianxiety drugs (anxiolytics), appetite suppressants, antimigraineagents, muscle contractants, anti-infectives (antibiotics, antivirals,antifungals, vaccines) antiarthritics, antimalarials, antiemetics,anepileptics, bronchodilators, cytokines, growth factors, anti-canceragents, antithrombotic agents, antihypertensives, cardiovascular drugs,antiarrhythmics, antioxicants, anti-asthma agents, hormonal agentsincluding contraceptives, sympathomimetics, diuretics, lipid regulatingagents, antiandrogenic agents, antiparasitics, anticoagulants,neoplastics, antineoplastics, hypoglycemics, nutritional agents andsupplements, growth supplements, antienteritis agents, vaccines,antibodies, diagnostic agents, and contrasting agents. The active agent,when administered by inhalation, may act locally or systemically.

[0051] The active agent may fall into one of a number of structuralclasses, including but not limited to small molecules, peptides,polypeptides, proteins, polysaccharides, steroids, proteins capable ofeliciting physiological effects, nucleotides, oligonucleotides,polynucleotides, fats, electrolytes, and the like.

[0052] Examples of active agents suitable for use in this inventioninclude but are not limited to one or more of calcitonin, amphotericinB, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme,cyclosporin, granulocyte colony stimulating factor (GCSF),thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin,granulocyte macrophage colony stimulating factor (GMCSF), growthhormone, human growth hormone (HGH), growth hormone releasing hormone(GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha,interferon beta, interferon gamma, interleukin-1 receptor,interleukin-2, interleukin-1 receptor antagonist, interleukin-3,interleukin-4, interleukin-6, luteinizing hormone releasing hormone(LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g.,mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which isincorporated herein by reference in its entirety), amylin, C-peptide,somatostatin, somatostatin analogs including octreotide, vasopressin,follicle stimulating hormone (FSH), insulin-like growth factor (IGF),insulintropin, macrophage colony stimulating factor (M-CSF), nervegrowth factor (NGF), tissue growth factors, keratinocyte growth factor(KGF), glial growth factor (GGF), tumor necrosis factor (TNF),endothelial growth factors, parathyroid hormone (PTH), glucagon-likepeptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin,phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates,respiratory syncytial virus antibody, cystic fibrosis transmembraneregulator (CFTR) gene, deoxyreibonuclease (Dnase),bactericidal/permeability increasing protein (BPI), anti-CMV antibody,13-cis retinoic acid, macrolides such as erythromycin, oleandomycin,troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin,flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin,leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide A;fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin,trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin,grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin,pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin,irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin,aminoglycosides such as gentamicin, netilmicin, paramecin, tobramycin,amikacin, kanamycin, neomycin, and streptomycin, vancomycin,teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin,colistimethate, polymixins such as polymixin B, capreomycin, bacitracin,penems; penicillins including penicllinase-sensitive agents likepenicillin G, penicillin V, penicillinase-resistant agents likemethicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin,nafcillin; gram negative microorganism active agents like ampicillin,amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonalpenicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin,and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten,ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin,cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor,cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime,cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone,cefotetan, cefinetazole, ceftazidime, loracarbef, and moxalactam,monobactams like aztreonam; and carbapenems such as imipenem, meropenem,pentamidine isethiouate, albuterol sulfate, lidocaine, metaproterenolsulfate, beclomethasone diprepionate, triamcinolone acetamide,budesonide acetonide, fluticasone, ipratropium bromide, flunisolide,cromolyn sodium, ergotamine tartrate and where applicable, analogues,agonists, antagonists, inhibitors, and pharmaceutically acceptable saltforms of the above. In reference to peptides and proteins, the inventionis intended to encompass synthetic, native, glycosylated,unglycosylated, pegylated forms, and biologically active fragments andanalogs thereof.

[0053] Active agents for use in the invention further include nucleicacids, as bare nucleic acid molecules, vectors, associated viralparticles, plasmid DNA or RNA or other nucleic acid constructions of atype suitable for transfection or transformation of cells, i.e.,suitable for gene therapy including anti sense. Further, an active agentmay comprise live attenuated or killed viruses suitable for use asvaccines. Other useful drugs include those listed within the Physician'sDesk Reference (most recent edition).

[0054] The amount of active agent in the pharmaceutical formulation willbe that amount necessary to deliver a therapeutically effective amountof the active agent per unit dose to achieve the desired result. Inpractice, this will vary widely depending upon the Particular agent, itsactivity, the severity of the condition to be treated, the patientpopulation, dosing requirements, and the desired therapeutic effect. Thecomposition will generally contain anywhere from about 1% by weight toabout 99% by weight active agent, typically from about 2% to about 95%by weight active agent, and more typically from about 5% to 85% byweight active agent, and will also depend upon the relative amounts ofadditives contained in the composition. The compositions of theinvention are particularly useful for active agents that are deliveredin doses of from 0.001 mg/day to 100 mg/day, preferably in doses from0.01 mg/day to 75 mg/day, and more preferably in doses from 0.10 mg/dayto 50 mg/day. It is to be understood that more than one active agent maybe incorporated into the formulations described herein and that the useof the term “agent” in no way excludes the use of two or more suchagents.

[0055] The pharmaceutical formulation may comprise a pharmaceuticallyacceptable excipient or carrier which may be taken into the lungs withno significant adverse toxicological effects to the subject, andparticularly to the lungs of the subject. In addition to the activeagent, a pharmaceutical formulation may optionally include one or morepharmaceutical excipients which are suitable for pulmonaryadministration. These excipients, if present, are generally present inthe composition in amounts ranging from about 0.01% to about 95% percentby weight, preferably from about 0.5 to about 80%, and more preferablyfrom about 1 to about 60% by weight. Preferably, such excipients will,in part, serve to further improve the features of the active agentcomposition, for example by providing more efficient and reproducibledelivery of the active agent, improving the handling characteristics ofpowders, such as flowability and consistency, and/or facilitatingmanufacturing and filling of unit dosage forms. In particular, excipientmaterials can often function to further improve the physical andchemical stability of the active agent, minimize the residual moisturecontent and hinder moisture uptake, and to enhance particle size, degreeof aggregation, particle surface properties, such as rugosity, ease ofinhalation, and the targeting of particles to the lung. One or moreexcipients may also be provided to serve as bulking agents when it isdesired to reduce the concentration of active agent in the formulation.

[0056] Pharmaceutical excipients and additives useful in the presentpharmaceutical formulation include but are not limited to amino acids,peptides, proteins, non-biological polymers, biological polymers,carbohydrates, such as sugars, derivatized sugars such as alditols,aldonic acids, esterified sugars, and sugar polymers, which may bepresent singly or in combination. Suitable excipients are those providedin WO 96/32096, which is incorporated herein by reference in itsentirety. The excipient may have a glass transition temperature (Tg)above about 35° C., preferably above about 40° C., more preferably above45° C., most preferably above about 55° C.

[0057] Exemplary protein excipients include albumins such as human serumalbumin (HSA), recombinant human albumin (rHA), gelatin, casein,hemoglobin, and the like. Suitable amino acids (outside of thedileucyl-peptides of the invention), which may also function in abuffering capacity, include alanine, glycine, arginine, betaine,histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine,isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine,tryptophan, and the like. Preferred are amino acids and polypeptidesthat function as dispersing agents. Amino acids falling into thiscategory include hydrophobic amino acids such as leucine, valine,isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine,histidine, and proline. Dispersibility-enhancing peptide excipientsinclude dimers, trimers, tetramers, and pentamers comprising one or morehydrophobic amino acid components such as those described above.

[0058] Carbohydrate excipients suitable for use in the inventioninclude, for example, monosaccharides such as fructose, maltose,galactose, glucose, D-mannose, sorbose, and the like; disaccharides,such as lactose, sucrose, trehalose, cellobiose, and the like;polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans,starches, and the like; and alditols, such as mannitol, xylitol,maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol,myoinositol and the like.

[0059] The pharmaceutical formulation may also include a buffer or a pHadjusting agent, typically a salt prepared from an organic acid or base.Representative buffers include organic acid salts of citric acid,ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinicacid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride,or phosphate buffers.

[0060] The pharmaceutical formulation may also include polymericexcipients/additives, e.g., polyvinylpyrrolidones, derivatizedcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylmethylcellulose, Ficolls (a polymeric sugar),hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin),polyethylene glycols, and pectin.

[0061] The pharmaceutical formulation may further include flavoringagents, taste-masking agents, inorganic salts (for example sodiumchloride), antimicrobial agents (for example benzalkonium chloride),sweeteners, antioxidants, antistatic agents, surfactants (for examplepolysorbates such as “TWEEN 20” and “TWEEN 80”), sorbitan esters, lipids(for example phospholipids such as lecithin and otherphosphatidylcholines, phosphatidylethanolamines), fatty acids and fattyesters, steroids (for example cholesterol), and chelating agents (forexample EDTA, zinc and other such suitable cations). Otherpharmaceutical excipients and/or additives suitable for use in thecompositions according to the invention are listed in “Remington: TheScience & Practice of Pharmacy”, 19^(th) ed., Williams & Williams,(1995), and in the “Physician's Desk Reference”, 52^(nd) ed., MedicalEconomics, Montvale, N.J. (1998), both of which are incorporated hereinby reference in their entireties.

[0062] “Mass median diameter” or “MMD” is a measure of mean particlesize, since the powders of the invention are generally polydisperse(i.e., consist of a range of particle sizes). MMD values as reportedherein are determined by centrifugal sedimentation, although any numberof commonly employed techniques can be used for measuring mean particlesize. “Mass median aerodynamic diameter” or “MMAD” is a measure of theaerodynamic size of a dispersed particle. The aerodynamic diameter isused to describe an aerosolized powder in terms of its settlingbehavior, and is the diameter of a unit density sphere having the samesettling velocity, generally in air, as the particle. The aerodynamicdiameter encompasses particle shape, density and physical size of aparticle. As used herein, MMAD refers to the midpoint or median of theaerodynamic particle size distribution of an aerosolized powderdetermined by cascade impaction.

[0063] In one version, the powdered formulation for use in the presentinvention includes a dry powder having a particle size selected topermit penetration into the alveoli of the lungs, that is, preferably 10μm mass median diameter (MMD), preferably less than 7.5 μm, and mostpreferably less than 5 μm, and usually being in the range of 0.1 μm to 5μm in diameter. The delivered dose efficiency (DDE) of these powders maybe greater than 30%, more preferably greater than 40%, more preferablygreater than 50% and most preferably greater than 60% and the aerosolparticle size distribution is about 1.0-5.0 μm mass median aerodynamicdiameter (MMAD), usually 1.5-4.5 μm MMAD and preferably 1.5-4.0 μm MMAD.These dry powders have a moisture content below about 10% by weight,usually below about 5% by weight, and preferably below about 3% byweight. Such powders are described in WO 95/24183, WO 96/32149, WO99/16419, and WO 99/16422, all of which are all incorporated herein byreference in their entireties.

[0064] Although the present invention has been described in considerabledetail with regard to certain preferred versions thereof, other versionsare possible, and alterations, permutations and equivalents of theversion shown will become apparent to those skilled in the art upon areading of the specification and study of the drawings. For example, therelative positions of the elements in the expedients for carrying outthe relative movements may be changed. Also, the various features of theversions herein can be combined in various ways to provide additionalversions of the present invention. Furthermore, certain terminology hasbeen used for the purposes of descriptive clarity, and not to limit thepresent invention. For example, the use of the terms such as “up” and“down” and “first” and “second” may be reversed in the specification.Therefore, the appended claims should not be limited to the descriptionof the preferred versions contained herein and should include all suchalterations, permutations, and equivalents as fall within the truespirit and scope of the present invention.

What is claimed is:
 1. An apparatus for filling a chamber, the apparatuscomprising: a hopper adapted to contain a powder pharmaceuticalformulation, the hopper comprising an outlet; and a disturbance membercapable of disturbing a medium within the hopper, the disturbance of themedium being sufficient to control the flow of powder through theoutlet, whereby the chamber may be filled by powder flowing through theoutlet and into the chamber.
 2. An apparatus according to claim 1wherein the medium comprises a gas.
 3. An apparatus according to claim 1wherein the medium comprises air.
 4. An apparatus according to claim 1wherein the disturbance member is a vibratable member capable ofgenerating vibrations within the hopper.
 5. An apparatus according toclaim 4 wherein the vibratable member comprises a membrane.
 6. Anapparatus according to claim 5 wherein the membrane is adapted tovibrate at a frequency selected to fluidize the powder.
 7. An apparatusaccording to claim 5 wherein the membrane is adapted to vibrate at afrequency selected to cause resonance within the container.
 8. Anapparatus according to claim 1 wherein the vibratable member is adaptedto vibrate at a frequency of from about 10 Hz to about 1000 Hz.
 9. Anapparatus according to claim 1 further comprising a powder vibratingmember.
 10. An apparatus according to claim 9 wherein the powdervibrating member comprises a member adapted to vibrate in contact withthe powder.
 11. An apparatus according to claim 9 wherein the powdervibrating member has a longitudinal axis and wherein the powdervibrating member vibrates in a direction parallel to the longitudinalaxis.
 12. An apparatus according to claim 1 wherein the chamber is achamber in a receptacle.
 13. An apparatus according to claim 12 whereinthe receptacle is a blister pack.
 14. An apparatus according to claim 12wherein the receptacle is a capsule.
 15. An apparatus according to claim1 further comprising the chamber and wherein the chamber is adapted totransport the powder to a receptacle.
 16. An apparatus according toclaim 15 wherein the chamber is a metering chamber.
 17. An apparatusaccording to claim 15 wherein the chamber is in a rotatable member. 18.An apparatus according to claim 17 wherein the rotatable member isrotatable between a powder receiving position and a powder ejectingposition.
 19. An apparatus according to claim 1 wherein the hoppercomprises an enclosure having side walls.
 20. An apparatus according toclaim 19 wherein the hopper comprises a cover and wherein the vibratablemember comprises a membrane in proximity to the cover.
 21. An apparatusaccording to claim 19 wherein the hopper comprises a cover and whereinthe cover comprises the vibratable member.
 22. An apparatus for fillinga chamber, the apparatus comprising: a hopper adapted to contain apowder pharmaceutical formulation, the hopper comprising an outlet; anda vibratable member positioned in, on, or near the hopper so that thevibratable member is spaced from powder in the hopper, the vibratablemember being capable of fluidizing the powder in the hopper, whereby thechamber may be filled with powder flowing through the outlet and intothe chamber.
 23. An apparatus according to claim 22 wherein thevibratable member comprises a membrane.
 24. An apparatus according toclaim 23 wherein the membrane is adapted to vibrate at a frequencyselected to fluidize the powder.
 25. An apparatus according to claim 22further comprising a second vibratable member.
 26. An apparatusaccording to claim 25 wherein the second vibratable member comprises amember adapted to contact the powder.
 27. An apparatus according toclaim 25 wherein the second vibratable member has a longitudinal axisand wherein the second vibratable member vibrates in a directionparallel to the longitudinal axis.
 28. An apparatus according to claim22 wherein the chamber comprises a receptacle.
 29. An apparatusaccording to claim 22 further comprising the chamber and wherein thechamber is adapted to transport the powder to a receptacle.
 30. Anapparatus according to claim 29 wherein the chamber is a meteringchamber.
 31. A method of filling a chamber, the method comprising:providing a powder pharmaceutical formulation in a hopper; disturbing amedium in the hopper to fluidize the powder; and passing the powderthrough an outlet and into the chamber.
 32. A method according to claim31 wherein the medium comprises a gas.
 33. A method according to claim31 wherein the medium comprises air.
 34. A method according to claim 31comprising disturbing the medium by generating vibrations within themedium.
 35. A method according to claim 34 wherein the vibrations aregenerated by vibrating a membrane.
 36. A method according to claim 35wherein the membrane is adapted to vibrate at a frequency selected tofluidize the powder so that the powder will pass through the outlet. 37.A method according to claim 36 wherein the membrane is vibrated at afrequency of from about 10 Hz to about 1000 Hz.
 38. A method accordingto claim 31 further comprising vibrating a member that is in contactwith the powder.
 39. A method according to claim 31 wherein the chambercomprises a receptacle and further comprising sealing the receptacle.40. A method according to claim 31 further comprising transferring thepowder from the chamber to a receptacle.
 41. A method according to claim31 comprising rotating the chamber from a powder receiving position to apowder ejecting position.
 42. A method of filling a chamber, the methodcomprising: providing a powder pharmaceutical formulation; vibrating amember spaced from the powder to fluidize the powder; and passing thepowder through an outlet and into the chamber.
 43. A method according toclaim 42 wherein the member is a membrane.
 44. A method according toclaim 43 wherein the membrane is adapted to vibrate at a frequencyselected to fluidize the powder so that the powder will pass through theoutlet.
 45. A method according to claim 42 wherein the powder isvibrated at a frequency of from about 10 Hz to about 1000 Hz.
 46. Amethod according to claim 42 further comprising vibrating a secondmember, the second member being in contact with the powder.
 47. Apharmaceutical package made by a process comprising: providing areceptacle; filling the receptacle with a powder pharmaceuticalformulation that has been fluidized by a fluidization member spaced fromthe powder; and sealing the receptacle to secure the powderpharmaceutical formulation therein.
 48. A pharmaceutical packageaccording to claim 47 wherein the receptacle comprises a blisterpackage.
 49. A pharmaceutical package according to claim 48 wherein theblister package comprises a lower layer comprising a cavity.
 50. Apharmaceutical package according to claim 49 wherein the blister packagecomprises an upper layer that is sealable onto the lower layer.
 51. Apharmaceutical package according to claim 50 wherein at least one of thelayers comprises a metal.
 52. A pharmaceutical package according toclaim 50 wherein both layers comprise a metal.
 53. A pharmaceuticalpackage according to claim 47 wherein the receptacle is at least aportion of a capsule.
 54. A pharmaceutical package according to claim 47wherein the receptacle is at least a portion of vial.
 55. Apharmaceutical package according to claim 47 wherein the receptacle is abottle.
 56. A pharmaceutical package according to claim 47 wherein thepackage is made by a process further comprising metering the powder in ametering chamber before filling the receptacle.
 57. A pharmaceuticalpackage according to claim 56 wherein the package is made by a processfurther comprising rotating the metering chamber.
 58. A pharmaceuticalpackage according to claim 47 wherein the package is made by a processwherein the pharmaceutical formulation is also fluidized by a vibratingmember in contact with the powder.